APPLICANT'S ABSTRACT: Liver Kupffer cells (KC) are the largest population of specialized macrophages in the body. They remove foreign materials from blood and produce a variety of important biological modifiers which effect not only the immune system but also other liver cells. Their unique location in the portal blood circulation draining the stomach and intestine causes KC to be exposed to variable and high concentrations of ethanol following alcohol ingestion. Previous studies in alcoholic humans and alcohol-fed animals report that chronic alcoholism suppresses KC phagocytic function. This consequence has been thought, in part, to cause increased susceptibility to serious infections. We have extensively studied the effects of ethanol on a variety of KC functions in vivo and in vitro and demonstrated that the effects are variable. Low concentrations stimulate phagocytosis, mitochondrial metabolism and synthesis of important cytokines such as tumor necrosis factor and interleukin-1. High concentrations of ethanol for prolonged periods are suppressive. Thus, the effects of ethanol on KC are complex and the consequences likely alter much more than only susceptibility to infection. This project proposes a series of investigations which will lead to a better understanding of the consequences of acute and chronic ethanol exposure on the KC. The studies involve cooperative effort by seven experienced investigators from four different departments in the Colleges of Medicine and Pharmacy. They build on the progress made over the past four years and investigate four unique new areas: 1) the effects of binge-type alcohol intake on KC function with and without concomitant continuous dietary ethanol ingestion; 2) characterization of KC function during the early period (0-48 hrs) following acute withdrawal of ethanol to determine if there is enhanced or supernormal KC phagocytosis, release of cytokines and elaboration of free radicals which could damage liver parenchymal cells; 3) determination of whether ethanol induces cytochrome P450 2E1 in KC and whether this contributes to ethanol impairment of KC function; and 4) characterization of the effects of acute and chronic ethanol ingestion on the intestinal immune system to test our hypothesis that alcohol consumption effects KC function partly by modifying release of regulatory cytokines from intestinal mucosa. These investigations will not only define the effects of ethanol on an important regulatory cell of that immune system, they will develop potential methods to counteract harmful effects of ethanol in humans.